Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma

Author:

Thudium Mueller Karen1,Grupp Stephan A.23,Maude Shannon L.23,Levine John E.45ORCID,Pulsipher Michael A.6ORCID,Boyer Michael W.7,August Keith J.8ORCID,Myers G. Doug8,Tam Constantine S.9,Jaeger Ulrich10ORCID,Foley Stephen Ronan11,Borchmann Peter12,Schuster Stephen J.13ORCID,Waller Edmund K.14ORCID,Awasthi Rakesh1,Potthoff Bernd15,Warren Andy16,Waldron Edward R.17,McBlane Fraser15,Chassot-Agostinho Andrea17,Laetsch Theodore W.1819ORCID

Affiliation:

1. Novartis Institutes for BioMedical Research, East Hanover, NJ;

2. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;

3. Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children’s Hospital of Philadelphia, Philadelphia, PA;

4. Department of Pediatrics, University of Michigan, Ann Arbor, MI;

5. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;

6. Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA;

7. Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City, UT;

8. Children’s Mercy Hospital, Kansas City, MO;

9. Peter MacCallum Cancer Center, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia;

10. Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria;

11. Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, ON, Canada;

12. Department of Haematology and Oncology, University Hospital of Cologne, Cologne, Germany;

13. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA;

14. Bone Marrow and Stem Cell Transplant Center, Winship Cancer Institute, Emory University, Atlanta, GA;

15. Novartis Pharma AG, Basel, Switzerland;

16. Salt River Integrated Bioanalysis GmbH, Basel, Switzerland;

17. Novartis Pharmaceuticals Corporation, East Hanover, NJ;

18. Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; and

19. Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Abstract

Abstract Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.

Publisher

American Society of Hematology

Subject

Hematology

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